Despite the widespread use of anti-retroviral therapy in AIDS patients, the prevalence of HIV-Associated Neurocognitive Disorders (HAND), including Asymptomatic Neurocognitive Impairment (ANI), Mild Neurocognitive Disorder (MND), and HIV-Associated Dementia (HAD), remains significantly high. Even mild forms of neurocognitive impairment may impact quality of life and antiretroviral drug adherence in H1V+ individuals (McArthur, 2004). The reason CNS complications may develop or persist in treated individuals is not known, but failure to eliminate viral reservoirs and inadequate drug penetration to the CNS could play a role in allowing low level viral replication to persist. For these reasons the development of novel compounds to treat HIV encephalitis (HIVE) is an objective of significant biomedical importance. In this project, we embark on proof-of-concept studies in nonhuman primates to test novel anti-Vif candidate drugs in support of efforts to accelerate basic and translational discoveries toward the advancement of new drug therapeutics for HAND. HIV-1 Vif is a highly attractive yet unrealized therapeutic target for the intervention of HlV-1 replication. HIV-1 Vif is essential for primate lentivirus replication in vitro. We have identified a lead Vif antagonist (RN18) that exhibits exquisite antiviral specificity against Vif-dependent viral replication. We plan to evaluate the in vivo efficacy ofthe most promising RN18 analogs in proof-of principal studies in a simian model of neuroAIDS. Vif antagonists with the most desirable antiviral activities, validated mechanism of action (Projects 1 and 2), and acceptable toxicity and pharmacokinetic profiles in rodents will be examined for in vivo antiviral activity in a monkey model of SIV-induced encephalitis (SIVE). We anticipate in vivo analysis of 2-3 Vif antagonists/year in groups of 6 animals each.